[go: up one dir, main page]

EP0582318B1 - Verwendung von Carnosolsäure wegen seiner anticarcinogenen und antiviralen Eigenschaften - Google Patents

Verwendung von Carnosolsäure wegen seiner anticarcinogenen und antiviralen Eigenschaften Download PDF

Info

Publication number
EP0582318B1
EP0582318B1 EP93115509A EP93115509A EP0582318B1 EP 0582318 B1 EP0582318 B1 EP 0582318B1 EP 93115509 A EP93115509 A EP 93115509A EP 93115509 A EP93115509 A EP 93115509A EP 0582318 B1 EP0582318 B1 EP 0582318B1
Authority
EP
European Patent Office
Prior art keywords
carnosic acid
solvent
extraction
extract
rosemary
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP93115509A
Other languages
English (en)
French (fr)
Other versions
EP0582318A1 (de
Inventor
Robert Aeschbach
Georges Philippossian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Societe des Produits Nestle SA
Nestle SA
Original Assignee
Societe des Produits Nestle SA
Nestle SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Societe des Produits Nestle SA, Nestle SA filed Critical Societe des Produits Nestle SA
Priority to ES93115509T priority Critical patent/ES2137963T3/es
Priority to AT93115509T priority patent/ATE184789T1/de
Priority to EP93115509A priority patent/EP0582318B1/de
Publication of EP0582318A1 publication Critical patent/EP0582318A1/de
Application granted granted Critical
Publication of EP0582318B1 publication Critical patent/EP0582318B1/de
Priority to GR990402510T priority patent/GR3031421T3/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the use of carnosic acid for its anticarcinogenic and antiviral properties.
  • Carnosic acid is a phenolic diterpene corresponding to the crude formula C20H2804 and having the structure I
  • Salvia and Rosmarinus species are constituent specific to Salvia and Rosmarinus species, where it is located mainly in leaves. It was first found by Linde in Salvia officinalis [Helv. Chim. Acta 47, 1234 (1962)] and by Wenkert et al. in Rosmarinus officinalis [J. Org. Chem. 30, 2931 (1965)]. Subsequently, he was identified positively in various other sage species, such as for example Salvia canariensis [Savona and Bruno, J. Nat. Prod. 46, 594 (1983)] or Salvia willeana [de la Torre and al, Phytochemistry 29, 668 (1990). he is also present in Salvia triloba and Salvia sclarea.
  • Carnosic acid is a powerful antioxidant [Brieskorn and Dömling, Z. Lebensm. Unters. Forsch. 141, 10 (1969)] and, according to a series of Russian works, where it is named salvine, an antibiotic against Staphylococcus aureus [CA 86, 117603r; 90, 49011b; 97, 67513r, 69163a, 69164b; 104, 221930w; 111, 130594t] and against certain microorganisms responsible for tooth decay and bad breath [CA 97, 84835q].
  • Prior art cites it to the subject of this last property for the preparation of toothpaste and water for mouth care [JP 59,103,665, Lion Corp.].
  • Carnosol is an oxidative artifact of carnosic acid. This oxidation takes place in the presence of oxygen, both after the rosemary or sage harvest in leaves left to air dry (we can also show that the freshly cut rosemary leaves do not contain of carnosol), only when these leaves are subjected to solvent extraction operations or that extracts themselves are subject to the classic operations of fractionation, enrichment and purification. There is any reason to believe that rosmanol, which has been identified in a fraction of rosemary subjected to a treatment alkaline, is also a subsequent product of oxidation carnosic acid, as well as Wenkert et al. the already suggested, as one could reasonably also assume it from rosmaridiphenol. Carnosic acid is therefore the only phenolic diterpene present in the native state in the rosemary and sage and as such is only entitled to the appellation natural product.
  • a process for obtaining carnosic acid from rosemary or sage is characterized by the fact that the spice is extracted with a non-polar solvent or a mixture of strong solvents apolarity, the extract obtained is subjected to a treatment selective adsorption on a solid support, we desorb carnosic acid with a polar solvent or a mixture of solvents with high polarity and the solvent is evaporated.
  • Carnosic acid like any catechol-like molecule (ortho-diphenol), is a reactive compound, very sensitive to oxidation, and therefore also very sensitive to all the operations usually performed, for isolation of natural substances (extraction, liquid-liquid partitioning, fractionation chromatographic, etc.).
  • carnosic acid is stable and can be handled without precautions excessive but that this obtaining in the form crystallized, can only be made from a preparation of plant material already enriched in acid carnosic.
  • the process according to the main request makes it possible to preserve the chemical integrity of carnosic acid because it does not that two processing steps, these steps spare the commodity and they are selective with respect to carnosic acid.
  • rosemary leaves or sage are extracted by a solvent basically apolar, so that the extract obtained contains, at side of all other apolar compounds or very little polar leaves of these plants, as the components essential oil, lipids, waxes, chlorophyll pigments and certain triterpenes, carnosic acid as practically the only compound of phenolic type passing into the extract.
  • the extraction rate carnosic acid is between 70 and 100% and its content in the extract is between 13 and 25%.
  • the previous extract is processed with an adsorbent solid having affinity for compounds with polar functions or having a particular selectivity towards the phenolic compounds, such as for example silica gel, aluminum oxide, to cite absorbent materials inorganic, or polyamide, polyvinylpyrolidone for cite examples of organic absorbent materials.
  • an adsorbent solid having affinity for compounds with polar functions or having a particular selectivity towards the phenolic compounds, such as for example silica gel, aluminum oxide, to cite absorbent materials inorganic, or polyamide, polyvinylpyrolidone for cite examples of organic absorbent materials.
  • carnosic acid is adsorbed with a high affinity or selectivity on the adsorbent, the other constituents of the extract essentially remaining in the liquid phase.
  • carnosic acid is desorbed from the adsorbent by contact with a solvent polar, which after evaporation gives a residue containing between 65 and 95% carnosic acid including, if necessary, the purification can still be completed by recrystallization.
  • the yield of carnosic acid in the production process is between 60 and 90%.
  • the starting plant material and the particle size plants play a role in the extraction yield of carnosic acid.
  • the residues obtained after hydrodistillation of the oil essential can also do the trick, but you should know that, this operation ending in significant losses of carnosic acid in product form of oxidation, the process for obtaining carnosic acid will be economically less favorable.
  • carnosic acid is more sage is easier than rosemary.
  • the explanation lies certainly in the fact that sage leaves are less fibrous than rosemary leaves. Rosemary is however a much more widespread plant than sage, and therefore constitutes a less expensive starting material and more readily available in large quantities.
  • the extraction solvent is also apolar as possible.
  • diethyl ether or a ketone (e.g. acetone), or an ester (e.g. ethyl acetate), or an alcohol (e.g. ethanol, methanol, etc.).
  • sage by example, it will be possible to extract quantitatively carnosic acid with a hydrocarbon solvent saturated. With all other material combinations plant / extraction variant, it will be necessary to use a solvent of slightly increased polarity if one want a good acid extraction rate carnosic.
  • the spice extraction step can be carried out either by solvent depletion of plant material, for example in a Soxhlet extractor (Variant I), either by charge, i.e. by immersion of the plant material in the solvent (Variant II), either by percolation or by pulsed column extraction, or by any other known technique of solid solvent extraction.
  • Variant I gives better carnosic acid extraction rate as variant II. However, it is more convenient to implement when it is necessary to extract significant quantities of material vegetable.
  • Extraction by solvent exhaustion is carried out in a Soxhlet type extractor composed of a reflux (flask + coolant), which contains the solvent extraction and between the two parts of which is interposed a siphon extractor fitted with a porous cartridge containing the plant material to be extracted.
  • a reflux flask + coolant
  • siphon extractor fitted with a porous cartridge containing the plant material to be extracted.
  • the vapors of solvent heated to boiling point in the flask along the extractor in a conduit fitted for this purpose and condense into liquid once they reach the refrigerant.
  • the condensed solvent falls back into the cartridge that it fills.
  • the extractor empties of its liquid content, who returns to the ball, taking with him some amount of vegetable matter dissolved.
  • the whole process can be defined as an extraction cycle.
  • the preferred solvents are for sage acyclic light hydrocarbons, e.g. petroleum ether, preferably at boiling range 40-60 ° C and for rosemary the same solvents or a binary combination of any of these with a solvent chlorinated, for example dichloromethane, in proportions volumes from 99 / l up to 9 / l.
  • the number of cycles applied to the material to be extracted are in the range of 5-20.
  • the solvent / vegetable matter proportions are preferably in a volume / weight ratio of 5 / l in the rosemary, and 10 / l in the case of sage (the higher amount of solvent in the case of sage is controlled by the much lower density of this compared to that of rosemary).
  • the preferred solvents in this extraction mode are for two vegetable materials sage and rosemary hydrocarbons aromatic, preferably toluene, or a combination binary of an acyclic light hydrocarbon, e.g. ether petroleum or hexane, with an oxygenated solvent, preferably ethanol or methanol, in proportions volumes from 99 / l up to 9 / l.
  • the first extraction step is carried out at a temperature between 20 and 50 ° C.
  • the plant extract obtained during the previous step is treated with an adsorbent material solid.
  • the carnosic acid in the extract is selectively adsorbed on solid matter, then the liquid phase discarded, is recovered in the concentrated state by desorption with a pure polar solvent, such as acetone, methanol, ethanol or ethyl acetate, or a mixture of one of these in significant proportion with a solvent apolar or slightly polar.
  • the liquid extract can be treated with any solid adsorbent with affinity or selectivity for this type of compound.
  • adsorbent materials that can be used for this purpose has already been given above. These materials are basically the ones we use commonly in separation techniques by liquid chromatography.
  • polyamide or any similar polymer such as polyvinylpyrrolidone
  • polyvinylpyrrolidone are materials of choice for adsorption of carnosic acid.
  • These materials indeed show a quite remarkable affinity for the place phenolic compounds (see eg "The Flavonoids", Harborne et al., Eds., Chapman and Hall, 1975, Chap. 1, p. 11).
  • these are chemically inert supports which are not likely to significantly alter the compounds with which they are brought into contact.
  • the liquid plant extract of the first process step can be brought into contact as is with the adsorbent material. If applicable, the extract will have been previously filtered to get rid of small amounts precipitated solids that could have possibly form during extraction or later to this one. In practice, however, we will have advantage to concentrate the liquid extract before putting it in contact with the adsorbent so as to promote passage of carnosic acid from the dissolved state to the state absorbed. In many cases, when the merger results in the formation of a precipitate solid, we prefer to completely remove the solvent extract and take up the residue in a second solvent chosen for its ability to dissolve easily and completely extract carnosic acid. In the practical, we have found that hydrocarbon-type solvents aromatic or chlorinated did the trick for this operation, toluene and dichloromethane being the preferred solvents.
  • the contact of the liquid extract with the material adsorbent can be achieved by immersion or by passing extract it through a column filled with material adsorbent.
  • This second technique is more effective and we then operates as follows: the liquid extract is loaded at the top of a column filled with material adsorbent conditioned with the same solvent as that of the extract. Once the extract is in contact with the material adsorbent, the column is washed with fresh solvent until all the material in the extract has been except the carnosic acid which remains adsorbed on the support. Carnosic acid is then desorbed from the material adsorbent by passing through the column a medium polar to polar solvent for example a mixing dichloromethane or toluene with ethanol or methanol. The solvent of the eluate and the residue can be further purified later by recrystallization to reach the degree of purity desired in carnosic acid.
  • the invention relates to the use of carnosic acid for the production of a composition or a diet intended to prevent or treat cancer.
  • Certain chemical compounds have properties which, directly or indirectly, reduce or remove mutagenic activity induced by other products chemicals.
  • free radicals are capable of inducing a large number of lesions different on DNA and that they are also involved in the process of cancer, aging and disease cardiovascular.
  • Carnosic acid has an action inhibitor of DNA damage caused by radicals free, which makes it possible to envisage its use for the prevention and treatment of cancer diseases or cardiovascular.
  • Dietetic or pharmaceutical compositions can be present in different forms adapted to the mode administration, for example, oral, enteral or parenteral.
  • the compositions are presented in the form of stabilized solutions or emulsions physically and chemically.
  • Physiological doses can be administered in the prevention or possibly treatment of certain forms of cancer and cardiovascular disease.
  • Carnosic acid can also be used for the manufacture of a composition intended for the treatment of herpes, which is a viral condition.
  • This composition can come in different forms adapted to the mode administration, for example orally or topical application.
  • We can for example prepare capsules, capsules or ointments. Physiological doses are used to treat this condition.
  • Table 1 illustrates the results obtained from a series of rosemary and sage extraction tests according to extraction variants I and II using the solvents described above.
  • Table 1 illustrates the results obtained from a series of rosemary and sage extraction tests according to extraction variants I and II using the solvents described above.
  • the more the polarity of the solvent increases (column 5), the better the rate of extraction of carnosic acid (column 8), but also the lower its concentration in the extract (column 7) and therefore the more ballast in the extract is considerable, this ballast being formed in particular from other phenolic compounds than carnosic acid and therefore capable of negatively interfering with it in the second step of the process.
  • 1 2 3 4 5 6 7 8 9 Example Mast. prem. AC content (%) Extraction variant Solvent extraction Extraction extraction rate (%) AC rate in (%) AC extraction rate (%) IQ extr.
  • a quality index (IQ) of the extract an index determined on the basis of criteria of efficiency and selectivity of the extraction solvent.
  • the efficiency (E) of the solvent is measured by the rate of extraction of carnosic acid (column 8). The more effective the solvent, the better the yield of carnosic acid recovered at the end of the process.
  • the selectivity (S) of the extraction solvent is measured by the content of carnosic acid in the extract (column 7), the more selective the solvent, the better the purity of the carnosic acid isolated at the end of the process.
  • the quality index (column 9) was relative to a scale of 100, arbitrarily considering as optimal the data of example 4.
  • the extract is dissolved in dichloromethane (150 ml) and, after filtering this solution to remove a weak proportion of insoluble matter, pour it on a column filled with polyamide and prepared from a suspension of 150 g of this material in 1 l of dichloromethane. Eluted with this same solvent to remove the extract materials not retained on the polyamide and corresponding to a strongly colored fraction (Fraction 1, 700 ml, 18 g of residue without solvent. continue elution with an 8/2 (v / v) mixture of dichloromethane / methanol. The transition zone between the two solvents is manifested on the column by the presence of a yellow ring-shaped area, which corresponds to the acid carnosic. We collect an intermediate fraction (Fraction 2, 700 ml, 2 g of residue without solvent), then the ring area (Fraction 3, 100 ml, 6.1 g of residue after have removed the solvent).
  • a extraction extractor is placed in the extraction container. Soxhlet a thin fabric stocking containing 383 g of rosemary ground with a carnosic acid content of 1.85% by weight. The height of the plant mass in the extractor measures 30 cm. The extractor is placed under an inert atmosphere and extracted with petroleum ether (2.5 l; PE 40-60 ° C) by 4 cycles in all of filling and siphoning of a duration of 75 min each. The solvent is evaporated off rotary and 35 g of dark oily extract are collected (Yield 9.1%), which contains 5.6 g (Yield 79%) carnosic acid.
  • the extract is dissolved in 240 ml of dichloromethane and pour the solution onto a polyamide column.
  • the antimutagenic activity of carnosic acid was evaluated in an Ames test in which the strain of Salmonella typhimurium TA 102 is used, which is known to respond easily to active oxygenated species. This strain is brought into contact with tert-butyl peroxide (tBOOH) known to generate peroxylated radicals and whose biological action is considered to be particularly advantageous since it generates oxygen radicals inside the cells. TBOOH produces a number of ad hoc alterations on the DNA of bacteria and the inhibition of these alterations produced by the antioxidant is measured when it is incorporated into the culture medium. The following antioxidants have been tested in a range of active doses: carnosic acid, carnosol and ascorbic acid.
  • tBOOH tert-butyl peroxide
  • the incubation medium is prepared by mixing 1 ml of bacterial suspension (5 ⁇ 10 9 bacteria / ml) of Salmonella typhimurium TA 102, prepared according to Maron and Ames [Mutation Research, 113, 175-215 (1983) ], 50 ⁇ l of saline buffer, 0.95 ml of 0.15 M KCl and 2.8 ml of Davis-Mingioli medium supplemented with 24 ⁇ g of histidine and 10 ⁇ g of biotin per ml.
  • the account of colonies of revertants and survivors is carried out on nutritious agar plates in the absence, respectively in the presence of histidine, and incubated for 3 days at 37 ° C, on which 0.1 ml of the previous bacterial suspension.
  • Entrance Compound IC50 (mg) IC50 (mM) Relative activity comparison of IC50 (mM) 1 Ac. carnosic 0.3 0.15 100 2 Carnosol 17.8 9.3 2 3 Ac. ascorbic 2.8 2.7 6
  • the antiviral activity of carnosic acid was tested in vitro at different concentrations (5; 2.5; 1.25; 0.62 ⁇ g / ml) against infectious batches of simple Herpes type 1 (HSV1) and type 2 (HSV2), and of Poliovirus type 3 (Polio 3), cultured on the VERO cell line. After 2 hours of incubation, the titers obtained are compared with that of the controls without inhibitor (Test 1). Aliquots of different test supernatants are then inoculated on new cells. After 4 days of incubation, the counting of the viral particles will allow this time to assess the viral production in the presence of the inhibitor (Test 2). Table 3 presents the results of these two tests. Concentration Ac.
  • test 1 show that the virus strain Polio 3 is not inhibited by carnosic acid. Through against the anti-HSV1 and anti-HSV2 action is quite significant since title reductions ranging up to 3 to 4 factors of ten are observed. So there is specific action of carnosic acid.
  • test 2 On finds that the production of Polio 3 can be considered as equivalent regardless of the acid concentration carnosic. However, the production of HSV1 and HSV2 is very affected. This confirms the specific action of the product, and also the absence of cellular toxicity since the highest concentration (5 ⁇ g / ml) the production of Polio 3 is not changed.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Anti-Oxidant Or Stabilizer Compositions (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Mobile Radio Communication Systems (AREA)
  • Transceivers (AREA)
  • Seasonings (AREA)

Claims (2)

  1. Verwendung von Carnosinsäure zur Herstellung einer Zusammensetzung oder eines Diätnahrungsmittels, die für die Vorbeugung oder Behandlung von Krebs bestimmt sind.
  2. Verwendung von Carnosinsäure für die Herstellung einer Zusammensetzung, die für die Behandlung von Herpes bestimmt ist.
EP93115509A 1990-10-06 1990-10-06 Verwendung von Carnosolsäure wegen seiner anticarcinogenen und antiviralen Eigenschaften Expired - Lifetime EP0582318B1 (de)

Priority Applications (4)

Application Number Priority Date Filing Date Title
ES93115509T ES2137963T3 (es) 1990-10-06 1990-10-06 Utilizacion del acido carnosico por sus propiedades anticarcinogenas y antiviricas.
AT93115509T ATE184789T1 (de) 1990-10-06 1990-10-06 Verwendung von carnosolsäure wegen seiner anticarcinogenen und antiviralen eigenschaften
EP93115509A EP0582318B1 (de) 1990-10-06 1990-10-06 Verwendung von Carnosolsäure wegen seiner anticarcinogenen und antiviralen Eigenschaften
GR990402510T GR3031421T3 (en) 1990-10-06 1999-10-07 Selective system scan for multizone radiotelephone subscriber units.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP90119218A EP0480077B1 (de) 1990-10-06 1990-10-06 Verfahren zur Gewinnung von Carnosäure
EP93115509A EP0582318B1 (de) 1990-10-06 1990-10-06 Verwendung von Carnosolsäure wegen seiner anticarcinogenen und antiviralen Eigenschaften

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
EP90119218.7 Division 1990-10-06
EP90119218A Division EP0480077B1 (de) 1990-10-06 1990-10-06 Verfahren zur Gewinnung von Carnosäure

Publications (2)

Publication Number Publication Date
EP0582318A1 EP0582318A1 (de) 1994-02-09
EP0582318B1 true EP0582318B1 (de) 1999-09-22

Family

ID=8204588

Family Applications (2)

Application Number Title Priority Date Filing Date
EP90119218A Expired - Lifetime EP0480077B1 (de) 1990-10-06 1990-10-06 Verfahren zur Gewinnung von Carnosäure
EP93115509A Expired - Lifetime EP0582318B1 (de) 1990-10-06 1990-10-06 Verwendung von Carnosolsäure wegen seiner anticarcinogenen und antiviralen Eigenschaften

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP90119218A Expired - Lifetime EP0480077B1 (de) 1990-10-06 1990-10-06 Verfahren zur Gewinnung von Carnosäure

Country Status (13)

Country Link
US (1) US5256700A (de)
EP (2) EP0480077B1 (de)
JP (2) JP2572173B2 (de)
AT (2) ATE184789T1 (de)
AU (1) AU634911B2 (de)
CA (1) CA2052745C (de)
DE (2) DE69033299T2 (de)
DK (2) DK0480077T3 (de)
ES (2) ES2060883T3 (de)
GR (1) GR3031421T3 (de)
IE (1) IE65512B1 (de)
NZ (1) NZ240094A (de)
ZA (1) ZA917484B (de)

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07500127A (ja) * 1991-09-20 1995-01-05 ノラック　テクノロジーズ　インコーポレイテッド 抗酸化剤オレオレジン組成物及びその製造方法
US5552158A (en) * 1993-02-23 1996-09-03 Norac Technologies Inc. Skin care composition
US5358752A (en) * 1993-02-23 1994-10-25 Norac Technologies Inc. Skin care composition
DE4418976C2 (de) * 1994-05-31 1996-12-12 Horst Walter Hendricks Phytotherapeutikum zur Behandlung von Infektionen des Herpes simplex-Virus (Typ 1 und Typ 2) und Verfahren zu seiner Herstellung
CA2220223C (en) * 1995-05-05 2008-07-29 Hauser Inc. High purity carnosic acid from rosemary and sage extracts by ph-controlled precipitation
DE69726612T2 (de) * 1997-04-16 2004-09-16 Lycored Natural Products Industies Ltd. Ein neues verfahren zur herstellung von stabilisierter carnosinsäure in hoher kontentration
US6824789B2 (en) 1998-05-20 2004-11-30 Kemin Industries, Inc. Method of extracting antioxidants from lamiaceae species and the extract products thereof
US6855349B2 (en) 1998-12-07 2005-02-15 Kemin Industries, Inc. Method for simultaneous extraction of essential oils and antioxidants from Labiatae species and the extract products thereof
KR100326841B1 (ko) * 1999-06-14 2002-03-04 박명규 들깨잎으로부터 고순도 로즈마리닉산의 분리, 정제방법
JP2001122777A (ja) 1999-10-27 2001-05-08 Nagase & Co Ltd 抗潰瘍剤
US6180144B1 (en) * 2000-01-27 2001-01-30 The Goodyear Tire & Rubber Co Chewing gum base stabilized with carnosic acid
JP2001233835A (ja) * 2000-02-28 2001-08-28 Nagase & Co Ltd カルノジン酸誘導体およびそれを用いた神経成長因子合成促進剤
US6450935B1 (en) 2000-10-13 2002-09-17 Kemin Industries, Inc. Method for removing essential oils and antioxidants from extract products of lamiaceae species using rolled film evaporation
JP2003073266A (ja) * 2001-08-30 2003-03-12 Osaka Organic Chem Ind Ltd 癌細胞増殖阻害剤
JP3980952B2 (ja) * 2002-04-12 2007-09-26 森下仁丹株式会社 植物抽出エキスを含有する腸溶性の脂肪吸収抑制剤およびそれを含有する食品
CN1297259C (zh) * 2004-05-21 2007-01-31 北京华医神农医药科技有限公司 一种来源于迷迭香的总二萜酚及其制备方法和用途
JP2006008531A (ja) * 2004-06-22 2006-01-12 Nagase & Co Ltd 抗酸化酵素産生促進剤及びその製造方法。
KR100668689B1 (ko) * 2004-11-09 2007-01-15 한국생명공학연구원 라이노바이러스에 대한 항바이러스 조성물
US20060134025A1 (en) * 2004-12-17 2006-06-22 Colgate-Palmolive Company Oral compositions containing extracts of Rosmarinus and related methods
KR100697309B1 (ko) * 2005-04-12 2007-03-20 한국생명공학연구원 식물 추출물을 포함하는 항바이러스 조성물
WO2008108825A2 (en) * 2006-10-10 2008-09-12 Burnham Institute For Medical Research Neuroprotective compositions and methods
KR20130103834A (ko) * 2006-11-17 2013-09-24 비오신테크 로즈마리 추출물을 포함하는 담배 필터 및 상기 필터를 사용하여 담배 연기 내의 유해 물질에 의해 유발되는 ｄｎａ 손상을 감소시키는 방법
CN103110188A (zh) * 2006-11-17 2013-05-22 生物合成技术公司 含有迷迭香提取物的卷烟过滤嘴以及通过使用所述过滤嘴减少由烟雾中有害物质引起的dna 损伤的方法
EP1925302A1 (de) 2006-11-24 2008-05-28 DSMIP Assets B.V. Diätetische oder pharmazeutische Zubereitung enthaltend trizyklische Diterpene und ihre Derivate zur Behandlung von Depression
EP1925301A1 (de) * 2006-11-24 2008-05-28 DSMIP Assets B.V. Verwendung von tricyclischen Diterpenen und deren Derivaten zur Behandlung oder Vorbeugung von entzündlichen - und/oder Gelenkerkrankungen
US8691247B2 (en) 2006-12-26 2014-04-08 Ad Lunam Labs Inc. Skin rejuvenation cream
FR2918560B1 (fr) * 2007-07-12 2009-10-09 Oreal Composition cosmetique contenant un derive de dibenzoylmethane et un compose phenanthrenol ; procede de photostabilisation du derive de dibenzoylmethane.
EP2381935B1 (de) * 2009-01-19 2016-06-01 Lycored Ltd. Synergistische kombinationen aus carotenoiden und polyphenolen
DE102009045994A1 (de) * 2009-10-26 2011-11-17 Evonik Degussa Gmbh Verfahren zur Herstellung eines carnosolsäurereichen Pflanzenextrakts
CN103189116B (zh) 2010-10-25 2015-01-14 卡拉马祖控股股份有限公司 使用绿色溶剂从唇形科草本植物中产生和分离水溶性和油溶性抗氧化矫味组分的简单方法
CN102070440B (zh) * 2010-12-15 2013-05-01 广东省食品工业研究所 一种富含鼠尾草酸的液态提取物的制备方法
ITGE20110041A1 (it) * 2011-04-12 2012-10-13 Ct Di Sperimentazione Ed Assist Enza Agricola Metodo di ottenimento di acido carnosico e triterpeni, come composti puri o come fitocomplessi arricchiti, da piante della famiglia delle lamiaceae
US9801844B2 (en) * 2012-05-24 2017-10-31 The Research Foundation Of The City University Of New York Methods and compositions for the treatment of cancer
CN104058955A (zh) * 2014-07-02 2014-09-24 中国林业科学研究院林产化学工业研究所 一种常压柱层析从迷迭香提取物中分离纯化鼠尾草酸的方法
CN107827738A (zh) * 2017-10-27 2018-03-23 湖南鑫利生物科技有限公司 一种从迷迭香提取物中分离鼠尾草酸的方法
CN107759467B (zh) * 2017-10-27 2020-11-13 湖南鑫利生物科技有限公司 一种提高迷迭香脂溶性抗氧化剂中鼠尾草酸含量的制备方法
TR201912820A2 (tr) 2019-08-26 2021-03-22 Tuerkiye Bilimsel Ve Teknolojik Arastirma Kurumu Tuebitak Karnosi̇k asi̇t, karnosol ve rozmari̇ni̇k asi̇t i̇zolasyon yöntemi̇
CN111100642B (zh) * 2019-12-06 2021-01-01 湖南鑫利生物科技有限公司 一种制备迷迭香脂溶性抗氧化剂结晶粉末的方法
BR112022019333A2 (pt) * 2020-03-26 2022-11-29 Johnson & Johnson Consumer Inc Composições compreendendo extratos de carum carvi e rosmarinus officinalis, e métodos para uso dos mesmos
CN116730830A (zh) * 2023-07-03 2023-09-12 苏州满元生物科技有限公司 一种从迷迭香中提取鼠尾草酸的方法
MA63860B1 (fr) * 2024-01-10 2025-10-31 Azerys Procédé d’extraction des antioxydants sous leur forme liquide par filtration à froid à partir de plantes de la famille des Lamiacées.
CN118236306B (zh) * 2024-05-23 2024-07-19 云南绿宝香精香料股份有限公司 一种艾叶提取物及其在化妆品中的应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4450097A (en) * 1981-02-26 1984-05-22 Lion Corporation Antioxidative compound, method of extracting same from rosemary, and use of same
US4638095A (en) * 1984-08-10 1987-01-20 Research Corporation Isolation of a novel antioxidant rosmaridiphenol from Rosmarinus officinalis L.
IL80783A0 (en) * 1986-10-17 1987-02-27 Univ Bar Ilan Food supplements
US5102659A (en) * 1990-07-12 1992-04-07 Shaklee Corporation Natural antioxidant compositions

Also Published As

Publication number Publication date
EP0480077A1 (de) 1992-04-15
ATE111434T1 (de) 1994-09-15
JPH04247054A (ja) 1992-09-03
ES2137963T3 (es) 2000-01-01
JP2880670B2 (ja) 1999-04-12
DK0480077T3 (da) 1995-02-13
JPH0873349A (ja) 1996-03-19
GR3031421T3 (en) 2000-01-31
IE913285A1 (en) 1992-04-08
US5256700A (en) 1993-10-26
DE69033299T2 (de) 2000-01-05
NZ240094A (en) 1994-02-25
IE65512B1 (en) 1995-11-01
ZA917484B (en) 1992-06-24
DE69012566D1 (de) 1994-10-20
JP2572173B2 (ja) 1997-01-16
DE69012566T2 (de) 1995-02-02
AU634911B2 (en) 1993-03-04
ES2060883T3 (es) 1994-12-01
CA2052745C (en) 2002-12-17
DK0582318T3 (da) 2000-03-20
AU8458891A (en) 1992-04-09
EP0582318A1 (de) 1994-02-09
CA2052745A1 (en) 1992-04-07
ATE184789T1 (de) 1999-10-15
DE69033299D1 (de) 1999-10-28
EP0480077B1 (de) 1994-09-14

Similar Documents

Publication Publication Date Title
EP0582318B1 (de) Verwendung von Carnosolsäure wegen seiner anticarcinogenen und antiviralen Eigenschaften
FR2550092A1 (fr) Preparation medicamenteuse solide a deux phases et son procede d'obtention
JPH0222755B2 (de)
JPS59219384A (ja) 天然抗酸化剤の製造方法
EP2285390B1 (de) Verfahren zur Gewinnung eines Extrakts aus Preiselbeertresten zur Prävention und Behandlung von Erkrankungen wie Karies, Zahnfleischentzündung oder Halsentzündung
FR2922549A1 (fr) Nouveaux composes d'antrodia camphorata.
FR2917408A1 (fr) Cyclohexenones d'antrodia camphorata pour le traitement de maladies auto-immunes et compositions pharmaceutiques les contenant
KR100528206B1 (ko) 항-일차-패스 효과 화합물
FR2749303A1 (fr) Procede d'extraction de polyphenols catechiques a partir de potentilles extrait obtenu et son utilisation
FR2940088A1 (fr) Composition antitussive et son procede de fabrication
FR2801792A1 (fr) Un nouveau medicament, le dihydromikanolide, son obtention par extraction de la plante mikania micrantha et son utilisation comme agent anti-proliferatif
CH635732A5 (fr) Procede de desamerisation d'un extrait de fruits ou de legumes et extrait desamerise obtenu.
EP0317453A1 (de) Medizinische Zusammensetzungen, gegründet auf Flavonoiden und Saponinen, gewonnen aus Chrysanthellum, Verfahren zu ihrer Herstellung und therapeutische Anwendungen
FR2940614A1 (fr) Utilisation antibacterienne d'un extrait de morus australis poir et du compose kuwanone h
KR100691805B1 (ko) 어호엔을 알코올 분해 효소 저해제로 사용하는 방법, 상기 어호엔을 포함하는 숙취 제거 조성물 및 상기 숙취 제거 조성물의 제조 방법
EP0707072A1 (de) Herstellung von Himbeerähnliche-Ketonen durch Biokonversion
US6589573B2 (en) Xanthine oxidase inhibitor and method for producing the same
EP0137862B1 (de) Verfahren zur Herstellung von Fettstoffen
KR100448680B1 (ko) 데커시놀을 유효성분으로 함유하는 숙취 해소용 조성물
JP3015363B1 (ja) ワカメ芽株を原料とする抗酸化食品素材の製造方法
JPH10304848A (ja) 抗高脂血症機能を持つ食品
WO2012156917A2 (fr) Procede d'obtention d'epsilon-viniferine et/ou de resveratrol et produits correspondants
EP0126691B1 (de) Verfahren zur Herstellung eines therapeutisch anwendbaren Extraktes aus Brackenridgea zanguebarica, Extrakt und entsprechendes Medikament
WO1996021739A1 (fr) Procede de preparation de derives de la butanone
WO2001056584A1 (fr) Procede de preparation d'extraits vegetaux, extraits ainsi obtenus et leurs utilisations

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19930925

AC Divisional application: reference to earlier application

Ref document number: 480077

Country of ref document: EP

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19980421

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AC Divisional application: reference to earlier application

Ref document number: 480077

Country of ref document: EP

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

REF Corresponds to:

Ref document number: 184789

Country of ref document: AT

Date of ref document: 19991015

Kind code of ref document: T

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19991020

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 19991027

Year of fee payment: 10

REF Corresponds to:

Ref document number: 69033299

Country of ref document: DE

Date of ref document: 19991028

ITF It: translation for a ep patent filed
GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)

Effective date: 19991207

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2137963

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

26N No opposition filed
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20001006

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20001031

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20060928

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20061003

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20061004

Year of fee payment: 17

Ref country code: GB

Payment date: 20061004

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20061011

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20061013

Year of fee payment: 17

Ref country code: CH

Payment date: 20061013

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20061031

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20061124

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20061213

Year of fee payment: 17

BERE Be: lapsed

Owner name: SOC. DES PRODUITS *NESTLE S.A.

Effective date: 20071031

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

EUG Se: european patent has lapsed
GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20071006

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 20080501

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071031

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20080501

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071006

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071031

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20080630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071007

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20080501

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071031

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20061010

Year of fee payment: 17

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071006

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20071008

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071031

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071008

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20071006